The National Institutes on Aging and Reagan Institute consensus criteria for the diagnosis of Alzheimer's disease includes a clinical evaluation of progressive dementia and a post-mortem observation of both amyloid plaques and neurofibrillary tangles in the brains of AD patients. Age of the patient is the largest risk for the presence of AD followed by the presence of one or more epsilon-4 alleles of the apolipoprotein-E gene (APOE4) in about 45 percent of all AD patients. The presence of APOE4 is also associated with an increase in the numbers of neurofibrillary tangles and amyloid plaques compared to those AD patients that lack APOE4 alleles. These data imply that increased numbers of plaques and tangles are associated with a gain of Alzheimer's dementia. An animal model that displays progressive dementia, amyloid plaques and neurofibrillary tangles is a critical step forward toward developing a safe and effective drug for the treatment of Alzheimer's disease. Based on reported studies of AD patients, an animal model should also display increased numbers of neurofibrillary tangles and amyloid plaques when APOE4 gene products are present. We propose to make a mouse model of Alzheimer's disease to meet the National Institute of Aging-Reagan Institute criteria for Alzheimer's disease. This triple transgenic mouse (APP + TAU + APOE) is designed to display both neurofibrilary tangles and amyloid plaques in their brains. To be an accurate model of human AD, we hypothesize that the numbers of neurofibrillary tangles and amyloid plaques should increase in the presence of human APOE4 gene products compared to human APOE3 gene products. Although work on plaque-only or tangle-only mice needs to continue, if we are really going to develop a mouse model of Alzheimer's disease, we must have progressive dementia, plaques, and tangles. Such a model would facilitate exploration of the basic mechanisms that cause neurodegeneration and dementia, in the 'presence of plaques, tangles and apoE proteins, and thus, greatly facilitate the finding of a safe and effective drug to block Alzheimer's dementia.